Dataset Information

Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes.

ABSTRACT:

Background

Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM.

Methods and results

We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions.

Conclusions

Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.

SUBMITTER: Tanaka A

PROVIDER: S-EPMC4338713 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes.

Tanaka Atsushi A Yuasa Shinsuke S Mearini Giulia G Egashira Toru T Seki Tomohisa T Kodaira Masaki M Kusumoto Dai D Kuroda Yusuke Y Okata Shinichiro S Suzuki Tomoyuki T Inohara Taku T Arimura Takuro T Makino Shinji S Kimura Kensuke K Kimura Akinori A Furukawa Tetsushi T Carrier Lucie L Node Koichi K Fukuda Keiichi K

Journal of the American Heart Association 20141111 6

<h4>Background</h4>Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potenti ...[more]

PMID: 25389285

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Project description:AimsDiastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. However, its cellular mechanisms are not fully understood, and presently there is no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the mechanisms underlying DD in HCM and as a platform for drug discovery.Methods and resultsIn the present study, beating iPSC-CMs were generated from healthy controls and HCM patients with DD. Micropatterned iPSC-CMs from HCM patients showed impaired diastolic function, as evidenced by prolonged relaxation time, decreased relaxation rate, and shortened diastolic sarcomere length. Ratiometric Ca2+ imaging indicated elevated diastolic [Ca2+]i and abnormal Ca2+ handling in HCM iPSC-CMs, which were exacerbated by β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[Ca2+]i) in HCM iPSC-CMs. These results were confirmed with genome-edited isogenic iPSC lines that carry HCM mutations, indicating that cytosolic diastolic Ca2+ overload, slowed [Ca2+]i recycling, and increased myofilament Ca2+ sensitivity, collectively impairing the relaxation of HCM iPSC-CMs. Treatment with partial blockade of Ca2+ or late Na+ current reset diastolic Ca2+ homeostasis, restored diastolic function, and improved long-term survival, suggesting that disturbed Ca2+ signalling is an important cellular pathological mechanism of DD. Further investigation showed increased expression of L-type Ca2+channel (LTCC) and transient receptor potential cation channels (TRPC) in HCM iPSC-CMs compared with control iPSC-CMs, which likely contributed to diastolic [Ca2+]i overload.ConclusionIn summary, this study recapitulated DD in HCM at the single-cell level, and revealed novel cellular mechanisms and potential therapeutic targets of DD using iPSC-CMs.

Project description:BackgroundMyocardial disarray is a likely focus for fatal arrhythmia in hypertrophic cardiomyopathy (HCM). This microstructural abnormality can be inferred by mapping the preferential diffusion of water along cardiac muscle fibers using diffusion tensor cardiac magnetic resonance (DT-CMR) imaging. Fractional anisotropy (FA) quantifies directionality of diffusion in 3 dimensions. The authors hypothesized that FA would be reduced in HCM due to disarray and fibrosis that may represent the anatomic substrate for ventricular arrhythmia.ObjectivesThis study sought to assess FA as a noninvasive in vivo biomarker of HCM myoarchitecture and its association with ventricular arrhythmia.MethodsA total of 50 HCM patients (47 ± 15 years of age, 77% male) and 30 healthy control subjects (46 ± 16 years of age, 70% male) underwent DT-CMR in diastole, cine, late gadolinium enhancement (LGE), and extracellular volume (ECV) imaging at 3-T.ResultsDiastolic FA was reduced in HCM compared with control subjects (0.49 ± 0.05 vs. 0.52 ± 0.03; p = 0.0005). Control subjects had a mid-wall ring of high FA. In HCM, this ring was disrupted by reduced FA, consistent with published histology demonstrating that disarray and fibrosis invade circumferentially aligned mid-wall myocytes. LGE and ECV were significant predictors of FA, in line with fibrosis contributing to low FA. Yet FA adjusted for LGE and ECV remained reduced in HCM (p = 0.028). FA in the hypertrophied segment was reduced in HCM patients with ventricular arrhythmia compared to patients without (n = 15; 0.41 ± 0.03 vs. 0.46 ± 0.06; p = 0.007). A decrease in FA of 0.05 increased odds of ventricular arrhythmia by 2.5 (95% confidence interval: 1.2 to 5.3; p = 0.015) in HCM and remained significant even after correcting for LGE, ECV, and wall thickness (p = 0.036).ConclusionsDT-CMR assessment of left ventricular myoarchitecture matched patterns reported previously on histology. Low diastolic FA in HCM was associated with ventricular arrhythmia and is likely to represent disarray after accounting for fibrosis. The authors propose that diastolic FA could be the first in vivo marker of disarray in HCM and a potential independent risk factor.

Dataset Information

Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes.

Background

Methods and results

Conclusions

Publications

Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes.

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